Long‐range diffusion of hyperpolarized 3He in rats

Based on a stimulated‐echo technique, a method to construct an apparent diffusion coefficient (ADC) map of hyperpolarized ³He in a long‐range diffusion scale is presented with a phase‐cycle alternative to remove all unwanted echoes. The approach was successfully applied to determine in vivo diffusion constants in rat lungs. The ADC values in healthy rats show a good agreement with reported values for diffusion times of ≈. These long diffusivity measurements may be sensitive to detect emphysema progression or tissue remodeling and thus have enormous potential for the diagnosis and tracking of disease progression and for drug evaluation. Magn Reson Med 61:54–58, 2009. © 2008 Wiley‐Liss, Inc.     

Dynamic spiral MRI of pulmonary gas flow using hyperpolarized (3)He: preliminary studies in healthy and diseased lungs.

An optimized interleaved-spiral pulse sequence, providing high spatial and temporal resolution, was developed for dynamic imaging of pulmonary ventilation with hyperpolarized (3)He, and tested in healthy volunteers and patients with lung disease. Off-resonance artifacts were minimized by using a short data-sampling period per interleaf, and gradient-fidelity errors were compensated for by using measured k-space trajectories for image reconstruction. A nonsequential acquisition order was implemented to improve image quality during periods of rapid signal change, such as early inspiration. Using a sliding-window reconstruction, cine-movies with a frame rate of 100 images per second were generated. Dynamic images demonstrating minimal susceptibility- and motion-induced artifacts were obtained in sagittal, coronal, and axial orientations. The pulse sequence had the flexibility to image multiple slices almost simultaneously. Our initial experience in healthy volunteers and subjects with lung pathology demonstrated the potential of this new tool for capturing the features of lung gas-flow dynamics.     

Time dependence of 3He diffusion in the human lung: measurement in the long-time regime using stimulated echoes.

A stimulated-echo-based technique was developed to measure the long-time-scale apparent diffusion coefficient (ADC) of hyperpolarized 3He during a single breath-hold acquisition. Computer simulations were used to evaluate the performance of the technique and guide the selection of appropriate parameter values for obtaining accurate ADC values. The technique was used in 10 healthy subjects and two subjects with chronic obstructive pulmonary disease (COPD) to measure the global ADC for diffusion times between a few tenths of a second and several seconds, and to acquire spatial maps of the ADC for a diffusion time of 1.5 s. The reproducibility of the technique and its sensitivity to the direction of diffusion sensitization were also investigated. In healthy subjects, global ADC values decreased by severalfold over the range of diffusion times measured (mean values = 0.039 and 0.023 cm2/s at diffusion times of 0.61 and 1.54 s, respectively). ADC maps were generally uniform, with mean values similar to the corresponding global values. For the two COPD subjects, global ADC values were substantially greater than those of every healthy subject at all diffusion times measured. In addition, regional elevations of ADC values were far more conspicuous on long-time-scale ADC maps than on short-time-scale ADC maps.     

Extending the range of diffusion times for regional measurement of the 3He ADC in human lungs.

A stimulated-echo-based technique was developed to measure the regional apparent diffusion coefficient (ADC) of hyperpolarized 3He during a single breathhold for diffusion times of 25 ms or greater. Compared to previous methods, a substantially shorter minimum diffusion time was achieved by decoupling diffusion sensitization from image acquisition. A hyperpolarized-gas phantom was used to validate the method, which was then tested in four healthy subjects in whom regional ADC maps were acquired with diffusion times of 50, 200, and 1500 ms and a tag wavelength of 5 or 10 mm. ADC values from healthy subjects were in good agreement with reported literature values and decreased with increasing diffusion time. Mean ADC values were approximately 0.07, 0.03, and 0.015 cm2/s for diffusion times of 50, 200, and 1500 ms, respectively. ADC maps were generally homogeneous, with similar mean values when measured with the same parameters in different subjects.     

Assessment of the lung microstructure in patients with asthma using hyperpolarized 3He diffusion MRI at two time scales: comparison with healthy subjects and patients with COPD

PURPOSE: To investigate short- and long-time-scale (3)He diffusion in asthma. MATERIALS AND METHODS: A hybrid MRI sequence was developed to obtain co-registered short- and long-time-scale apparent diffusion coefficient (ADC) maps during a single breath-hold. The study groups were: asthma (n = 14); healthy (n = 14); chronic obstructive pulmonary disease (COPD) (n = 9). Correlations were made between mean-ADC and %ADC-abn (abnormal) (%pixels with ADC > mean +2 SD of healthy) at both time scales and spirometry. Sensitivities were determined using receiver operating characteristic (ROC) analysis. RESULTS: For asthmatics, the short- and long-time-scale group-mean ADCs were 0.254 +/- 0.032 cm(2)/s and 0.0237 +/- 0.0055 cm(2)/s, respectively, representing a 9% and 27% (P = 0.038 and P = 0.005) increase compared to the healthy group. The group-mean %ADC-abn were 6.4% +/- 3.7% and 17.5% +/- 14.2%, representing a 107% and 272% (P = 0.004 and P = 0.006) increase. For COPD much greater elevations were observed. %ADC-abn provided better discrimination than mean-ADC between asthmatic and healthy subjects. In asthmatics ADC did not correlate with spirometry. CONCLUSION: With long-time scale (3)He diffusion magnetic resonance imaging (MRI) changes in lung microstructure were detected in asthma that more conspicuous regionally than at the short time scale. The hybrid diffusion method is a novel means of identifying small airway disease.     

Magnetization tagging decay to measure long-range (3)He diffusion in healthy and emphysematous canine lungs.

Spatial modulation (tagging) of the longitudinal magnetization allows diffusive displacements to be measured over times approximately as long as T(1) and over correspondingly long distances. Magnetization tagging is used here with hyperpolarized (3)He gas in canine lungs with unilateral elastase-induced emphysema. A new scheme for analyzing images subsequent to tagging determines the spatially-resolved fractional modulation and its decay rate, using a sliding window. The diffusivity so determined over seconds and centimeter lengths, D(sec), is smaller in all cases than the diffusivity measured over milliseconds and hundreds of microns, D(msec) (in healthy lungs, this ratio is about 0.1). While D(msec) is sensitive to lung microstructure on the alveolar level, D(sec) reflects airway connectivity and provides new information on lung structure. The results show substantial increases in D(sec) in the lungs of four dogs with clear evidence of emphysema. For these dogs, the fractional increase in long-range diffusivity D(sec) in the emphysematous lungs was greater than that in short-range diffusivity D(msec).     

Effects of ozone exposure in rat lungs investigated with hyperpolarized 3 He MRI

PURPOSE: To investigate the effects of subchronic ozone exposure on rat lung ventilation using hyperpolarized (HP) (3)He MRI. MATERIALS AND METHODS: A total of 24 Sprague-Dawley rats, distributed in one control group and four groups exposed to 0.5 ppm ozone concentration for two days or six days, either continuously (22 hours/day) or alternatingly (12 hours/day). A three-step MRI protocol was designed and applied to each animal, including: 1) (3)He gas distribution images acquired at inspiratory capacity, 2) measurements of intrapulmonary (3)He diffusion coefficients, and 3) dynamic ventilation acquisitions performed during lung filling with (3)He. RESULTS: No differentiation between animals exposed to ozone and control animals was observed from the ventilation images obtained at inspiratory capacity. The (3)He diffusion coefficients were not statistically different from one group to another. Ventilation defects, appearing as delayed lung filling regions and heterogeneous lung filling, were observed in the dynamic lung ventilation image series. The percentage of animals with ventilation defects in the control, two-day, and six-day exposed groups were equal to 20%, 43% and 75%, respectively. In the subgroup of the animals exposed six days for 12 hours per day, the percentage of animals exhibiting ventilation defects was equal to 85%. CONCLUSION: Heterogeneous obstructive patterns in an experimental animal model of subchronic ozone exposure were observed using HP (3)He MRI.     

Detection of age-dependent changes in healthy adult lungs with diffusion-weighted 3He MRI

RATIONALE AND OBJECTIVES: To investigate changes in lung microstructure in healthy adult subjects with no smoking history using diffusion-weighted 3He MRI. MATERIALS AND METHODS: Diffusion magnetic resonance imaging using hyperpolarized helium 3 (3He) was applied to healthy volunteers to explore the dependence of lung microstructural changes with age, reflected by changes in the apparent diffusion coefficient (ADC) of 3He in lung air spaces. Data from three sites (University of Virginia (UVa), N = 25; University of Wisconsin (UW), N = 8; University of Nottingham (UN), N = 11) were combined in pooled analysis, including a total of N = 44 subjects (age range, 18-69 years; average age, 41.7 +/- 16.7 years). RESULTS: ADC was found to depend on age at all three sites (UW, R = +0.95, P = .0003; UVa, R = +0.74, P < .0001; UN, R = +0.96, P < .0001). Increases in mean ADCs with age appeared similar across sites (UW, +0.0017 cm2 s(-1) y(-1); UVa, +0.0015 cm2 s(-1) y(-1); pooled, +0.0015 cm2 s(-1) y(-1); P = .71). In a regional analysis performed on UW data, the increase in ADC affected all regions of the lung, but the apical and middle regions showed a greater increase compared with the base of the lung. CONCLUSION: Results suggest the observed age dependence of the ADC may be caused by changes in lung microstructure that increase alveolar volume during the aging process.     

Helium-3 diffusion MR imaging of the human lung over multiple time scales

RATIONALE AND OBJECTIVES: Diffusion magnetic resonance imaging (MRI) with hyperpolarized (3)He gas is a powerful technique for probing the characteristics of the lung microstructure. A key parameter for this technique is the diffusion time, which is the period during which the atoms are allowed to diffuse within the lung for measurement of the signal attenuation. The relationship between diffusion time and the length scales that can be explored is discussed, and representative, preliminary results are presented from ongoing studies of the human lung for diffusion times ranging from milliseconds to several seconds. MATERIALS AND METHODS: (3)He diffusion MRI of the human lung was performed on a 1.5T Siemens Sonata scanner. Using gradient echo-based and stimulated echo-based techniques for short and medium-to-long diffusion times, respectively, measurements were performed for times ranging from 2 milliseconds to 6.5 seconds in two healthy subjects, a subject with subclinical chronic obstructive pulmonary disease and a subject with bronchopulmonary dysplasia. RESULTS: In healthy subjects, the apparent diffusion coefficient decreased by about 10-fold, from approximately 0.2 to 0.02 cm(2)/second, as the diffusion time increased from approximately 1 millisecond to 1 second. Results in subjects with disease suggest that measurements made at diffusion times substantially longer than 1 millisecond may provide improved sensitivity for detecting certain pathologic changes in the lung microstructure. CONCLUSIONS: With appropriately designed pulse sequences it is possible to explore the diffusion of hyperpolarized (3)He in the human lung over more than a 1,000-fold variation of the diffusion time. Such measurements provide a new opportunity for exploring and characterizing the microstructure of the healthy and diseased lung.     

Functional MRI of the lung using hyperpolarized 3-helium gas

Lung imaging has traditionally relied on x-ray methods, since proton MRI is limited to some extent by low proton density in the lung parenchyma and static field inhomogeneities in the chest. The relatively recent introduction of MRI of hyperpolarized noble gases has led to a rapidly evolving field of pulmonary MRI, revealing functional information of the lungs, which were hitherto unattainable. This review article briefly describes the physical background of the technology, and subsequently focuses on its clinical applications. Four different techniques that have been used in various human investigations are discussed: ventilation distribution, ventilation dynamics, and small airway evaluation using diffusion imaging and oxygen uptake assessment.     

An evaluation of pulmonary atelectasis and its re-expansion: hyperpolarized 3He MRI in the Yorkshire pig

Rationale and Objectives. Atelectasis, the collapse of small airways, is a significant clinical problem. We use hyperpolarized (HP) ³He magnetic resonance imaging (MRI), or HP ³He MRI, to describe atelectasis in the normal Yorkshire pig, the pig with atelectasis, and the pig with re-expansion of atelectasis. We compare HP ³He MRI findings with depictions of atelectasis by proton MRI.Materials and Methods. During end-expiration in the anesthetized and paralyzed Yorkshire pig (n = 6), HP ³He gas produced by the optical pumping spin-exchange method, was delivered via an endotracheal tube. For two separate groups, atelectasis was either induced by Fogarty-catheter occlusion balloon inflation (n = 3), or lateral chest wall administration of sodium hydroxide (NaOH) (n = 3). MRI was performed at time zero, at 5, 9, 13, 15, and 19 minutes after atelectasis production, 30 minutes after balloon deflation, and 10 and 30 minutes after recruitment of atelectatic areas with increased tidal volumes and added positive end-expiratory pressure. High-resolution, cross-sectional MR images were procured, and comparison was made with the traditional proton MRI.Results. Atelectatic areas by HP ³He MRI were easily distinguishable in both subject groups, and correlated with those located by proton MR. HP ³He MR images showed absence of ventilation, whereas proton MR images depicted dense, white areas. Re-expansion of atelectasis was well delineated by HP ³He MRI.Conclusion. HP ³He MRI may overcome many of the shortcomings of other well-established radiographic methods. HP ³He MRI is a novel, informative method for describing atelectasis and its re-expansion.     

Compressed sensing in hyperpolarized 3He Lung MRI

In this work, the application of compressed sensing techniques to the acquisition and reconstruction of hyperpolarized ³He lung MR images was investigated. The sparsity of ³He lung images in the wavelet domain was investigated through simulations based on fully sampled Cartesian two‐dimensional and three‐dimensional ³He lung ventilation images, and the k‐spaces of 2D and 3D images were undersampled randomly and reconstructed by minimizing the L1 norm. The simulation results show that temporal resolution can be readily improved by a factor of 2 for two‐dimensional and 4 to 5 for three‐dimensional ventilation imaging with ³He with the levels of signal to noise ratio (SNR) (～19) typically obtained. The feasibility of producing accurate functional apparent diffusion coefficient (ADC) maps from undersampled data acquired with fewer radiofrequency pulses was also demonstrated, with the preservation of quantitative information (mean ADC_cs ～ mean ADC_full ～ 0.16 cm² sec^?1). Prospective acquisition of 2‐fold undersampled two‐dimensional ³He images with a compressed sensing k‐space pattern was then demonstrated in a healthy volunteer, and the results were compared to the equivalent fully sampled images (SNR_cs = 34, SNR_full = 19). Magn Reson Med 63:1059–1069, 2010. © 2010 Wiley‐Liss, Inc.     

Imaging lung microstructure in mice with hyperpolarized 3He diffusion MRI

Quantitative measurement of lung microstructure is of great significance in assessment of pulmonary disease, particularly in the earliest stages. The technique for MRI‐based ³He lung morphometry was previously developed and validated for human lungs, and was recently extended to ex vivo mouse lungs. The technique yields accurate, quantitative information about the microstructure and geometry of acinar airways. In this study, the ³He lung morphometry technique is successfully implemented for in vivo studies of mice. Results indicate excellent agreement between in vivo morphometry via ³He MRI and microscopic morphometry after sacrifice. This opens up new avenues for application of the technique as a precise, noninvasive, in vivo biomarker of changes in lung microstructure, within various mouse models of lung disease. Magn Reson Med, 2011. © 2010 Wiley‐Liss, Inc.     

Quantitative assessment of emphysema using hyperpolarized 3He magnetic resonance imaging.

In this experiment, Sprague-Dawley rats with elastase-induced emphysema were imaged using hyperpolarized (3)He MRI. Regional fractional ventilation r, the fraction of gas replaced with a single tidal breath, was calculated from a series of images in a wash-in study of hyperpolarized gas. We compared the regional fractional ventilation in these emphysematous rats to the regional fractional ventilations we calculated from a previous baseline study in healthy Sprague-Dawley rats. We found that there were differences in the maps of fractional ventilation and its associated frequency distribution between the healthy and emphysematous rat lungs. Fractional ventilation tended to be much lower in emphysematous rats than in normal rats. With this information, we can use data on fractional ventilation to regionally distinguish between healthy and emphysematous portions of the lung. The successful implementation of such a technique on a rat model could lead to work toward the future implementation of this technique in human patients.     

A short‐breath‐hold technique for lung pO2 mapping with 3He MRI

A pulse‐sequence strategy was developed for generating regional maps of alveolar oxygen partial pressure (pO₂) in a single 6‐sec breath hold, for use in human subjects with impaired lung function. Like previously described methods, pO₂ values are obtained by measuring the oxygen‐induced T₁ relaxation of inhaled hyperpolarized ³He. Unlike other methods, only two ³He images are acquired: one with reverse‐centric and the other with centric phase‐encoding order. This phase‐encoding arrangement minimizes the effects of regional flip‐angle variations, so that an accurate map of instantaneous pO₂ can be calculated from two images acquired a few seconds apart. By combining this phase‐encoding strategy with variable flip angles, the vast majority of the hyperpolarized magnetization goes directly into the T₁ measurement, minimizing noise in the resulting pO₂ map. The short‐breath‐hold pulse sequence was tested in phantoms containing known O₂ concentrations. The mean difference between measured and prepared pO₂ values was 1 mm Hg. The method was also tested in four healthy volunteers and three lung‐transplant patients. Maps of healthy subjects were largely uniform, whereas focal regions of abnormal pO₂ were observed in diseased subjects. Mean pO₂ values varied with inhaled O₂ concentration. Mean pO₂ was consistent with normal steady‐state values in subjects who inhaled ³He diluted only with room air. Magn Reson Med 63:127–136, 2010. © 2009 Wiley‐Liss, Inc.     

Improved technique for measurement of regional fractional ventilation by hyperpolarized 3He MRI

Quantitative measurement of regional lung ventilation is of great significance in assessment of lung function in many obstructive and restrictive pulmonary diseases. A new technique for regional measurement of fractional ventilation using hyperpolarized ³He MRI is proposed, addressing the shortcomings of an earlier approach that limited its use to small animals. The new approach allows for the acquisition of similar quantitative maps over a shortened period and requires substantially less ³He gas. This technique is therefore a better platform for implementation in large species, including humans. The measurements using the two approaches were comparable to a great degree, as verified in a healthy rat lung, and are very reproducible. Preliminary validation is performed in a lung phantom system. Volume dependency of measurements was assessed both in vivo and in vitro. A scheme for selecting an optimum flip angle is proposed. In addition, a dead space modeling approach is proposed to yield more accurate measurements of regional fractional ventilation using either method. Finally, sensitivity of the new technique to model parameters, noise, and number of included images were assessed numerically. As a prelude to application in humans, the technique was implemented in a large animal study successfully. Magn Reson Med, 2010. © 2009 Wiley‐Liss, Inc.     

Multiple regression method for pulmonary apparent diffusion coefficient measurement by hyperpolarized 3He MRI

PURPOSE: To develop and validate a new multiple regression technique for the separation of flip angle effect in pulmonary apparent diffusion coefficient (ADC) measurement. MATERIALS AND METHODS: Hyperpolarized (3)He MRI (HP (3)He MRI) ADC measurements were performed on phantom, pig, and human models. The diffusion-sensitization sequence is modified from a standard gradient echo (GRE) sequence with a nonlinear progression in the bipolar gradient amplitude with each image. In the self-diffusion phantom experiment, four images were acquired with base gradient factor b(0) = 0.15 second/cm(2); in the pig and human experiment, six images were acquired with base gradient factor b(0) = 1.4 second/cm(2). RESULTS: The self-diffusion coefficient measured in the phantom experiment was 1.98 +/- 0.16 cm(2)/second. The measured uncertainty curve was consistent with the theoretically predicted curve. The measured in vivo ADC values (three coronal slices in the supine direction) were 0.20/0.16/0.13 cm(2)/second and 0.20/0.18/0.16 cm(2)/second for pig and human experiments, respectively. CONCLUSION: With the introduction of a nonlinear progression in the diffusion-sensitization gradients, the multiple regression technique is capable of separating the flip angle effect in ADC measurement. In addition, this technique can perform a rigorous measurement uncertainty analysis and provide the optimal scan parameters that yield best noise performance.     

Simultaneous measurement of pulmonary partial pressure of oxygen and apparent diffusion coefficient by hyperpolarized 3He MRI

Hyperpolarized ³He (HP ³He) MRI shows promise to assess structural and functional pulmonary parameters in a sensitive, regional, and noninvasive way. Structural HP ³He MRI has applied the apparent diffusion coefficient (ADC) for the detection of disease‐induced lung microstructure changes at the alveolar level, and HP ³He pulmonary partial pressure of oxygen (pO₂) imaging measures the oxygen transfer efficiency between the lung and blood stream. Although both parameters are affected in chronic obstructive pulmonary disease (COPD), a quantitative assessment of the regional correlation of the two parameters has not been reported in the literature. In this work, a single acquisition technique for the simultaneous measurement of ADC and pO₂ is presented. This technique is based on the multiple regression method, in which a general linear estimator is used to retrieve the values of ADC and pO₂ from a series of measurements. The measurement uncertainties are also analytically derived and used to find an optimal measurement scheme. The technique was first tested on a phantom model, and then on an in vivo normal pig experiment. A case study was performed on a COPD patient, which showed that in a region of interest ADC was 29% higher while oxygen depletion rate was 61% lower than the corresponding global average values. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.